Economic evaluation of physical activity interventions for type 2 diabetes management: a systematic review

Abstract Background Economic evaluation of physical activity interventions has become an important area for policymaking considering the high costs attributable to physical inactivity. However, the evidence for such interventions targeting type 2 diabetes control is scarce. Therefore, the present study aimed to synthesize economic evaluation studies of physical activity interventions for type 2 diabetes management. Methods A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement (PROSPERO reference number CRD42021231021). An electronic search was performed in PubMed, Web of Science, Cochrane Library and NHS Economic Evaluation Database. Studies were eligible if they included: adults with type 2 diabetes; any physical activity intervention in the community settings; an experimental or quasi-experimental design; and a parameter of economic evaluation [cost analysis of interventions, cost-effectiveness analysis (including cost-utility analysis) and cost-benefit analysis] as an outcome. Results Ten studies were included in this review: seven were randomized controlled trials and three were quasi-experimental studies. All studies included direct costs, and four also included indirect costs. Four studies demonstrated that physical activity interventions were cost-saving, six studies showed cost-effectiveness, and two studies reported cost-utility. The estimates varied considerably across the studies with different analytical and methodological approaches. Conclusion Overall, this systematic review found that physical activity interventions are a worth investment for type 2 diabetes management. However, comparability across interventions was limited due to heterogeneity in interventions type, design and delivery, which may explain the differences in the economic measures.

Introduction D iabetes is a major public health challenge of the century. In the last two decades, the prevalence of diabetes has increased alarmingly worldwide. 1 In 2021, it was estimated that 537 million adults aged 20-79 years were diagnosed with diabetes. 1 Obesity and physical inactivity have been associated with the increase in the prevalence of type 2 diabetes (T2D)-which accounts for around 90% of all diabetes cases worldwide. 1 Physical activity is critical to the prevention and management of T2D. 2,3 Studies have shown that physical activity decreases glycated hemoglobin, insulin resistance, fasting blood glucose, body mass index, body fat, blood lipids and blood pressure. [4][5][6] Unfortunately, most people living with T2D remain physically inactive, 7,8 and are, therefore, missing the opportunities to capitalize on the benefits, such as the reduced risk of cardiovascular events and overall mortality, 9,10 and lowered healthcare costs. Recent studies showed that physical inactivity is costly and associated with a considerable disease burden. 11 In 2013, physical inactivity was estimated to cost the healthcare system $53.8 billion globally, and, T2D to cost $37.6 billion to the healthcare system. Physical inactivity-related deaths also contributed to at least $13.7 billion in productivity losses and were responsible for 13.4 million disability-adjusted life-years worldwide. 12 The economic evaluation of physical activity interventions plays an important role in informing policymaking and resource allocation, considering the constrained resources and competing priorities. In recent years, the economic evaluation of physical activity interventions has become an increasingly common practice. Evidence shows that some physical activity interventions are very cost-effective, such as various school-based interventions among children and adolescents, interventions using pedometers among adults, fall prevention programs among older people, and mass media campaigns and environmental approaches for the general population. 13 Among people living with T2D, studies have found a varying degree of cost-effectiveness. 14,15 Examples of interventions include intensive hypertension control in individuals with T2D (e.g. angiotensin-converting enzyme inhibitor therapy for intensive hypertension control compared with standard hypertension control); the use of pioglitazone plus metformin, a reportedly cost-saving therapy when compared with rosiglitazone plus metformin; comprehensive foot care to prevent ulcers compared with the usual care; counseling and treatment for smoking cessation compared with no counseling and treatment; intensive glycemic control in persons with newly diagnosed T2D compared with conventional glycemic control. 14,15 However, evidence regarding the economic evaluation of physical activity interventions for T2D management remains scarce. Therefore, we aim to systematically review economic evaluation studies of physical activity interventions for T2D management. Specifically, we aimed to summarize cost analysis of interventions (CAI), cost-effectiveness analysis (CEA) (including cost-utility analyses [CUA]), and cost-benefit analysis (CBA) of physical activity interventions in T2D.
By synthesizing and critically appraising existing economic evaluation studies of physical activity interventions in T2D, this study intends to assist decision makers with resource allocation and intervention selection. 16

Methods
This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement 17 (Supplementary file S1). The protocol of this systematic review was registered in PROSPERO-reference number CRD42021231021.

Eligibility criteria
Studies were eligible if participants were adults diagnosed with T2D; included any physical activity intervention in the community settings; included experimental and quasi-experimental studies; outcome measures included a parameter of economic evaluation-CAI, CEA (including CUA) or CBA.
We excluded studies with multicomponent interventions (e.g. combined physical activity and diet), and studies with multimorbidity including T2D but without separate data for T2D.

Information sources
Electronic searches were conducted in PubMed, Web of Science, Cochrane Library and NHS Economic Evaluation Database.

Search strategy
For database search, we used the following keywords: ('physical activity' OR exercise OR 'active transport' OR 'active mobility' OR 'active commuting' OR 'active travel' OR walking OR cycling OR running OR training OR sport*) AND (diabet* OR 'glycemic control' OR 'glycaemic control' OR 'glucose control') AND (cost* OR costeffectiveness OR cost-utility OR cost-benefit OR 'economic evaluation' OR 'economic analysis' OR 'economic assessment' OR 'economic impact'). We did not apply language and date limits to the searches.
Detailed search strategy is available in Supplementary file S2.

Selection process
Two authors (A.B. and R.M.) independently reviewed the search results and screened records retrieved from databases according to predefined steps. First, records were screened based on the information from the title and abstract. Second, potentially relevant articles were retrieved for full-text reading and to determine their eligibility. In case of disagreement, the consensus was reached through discussion.

Data collection process
Two authors (A.B. and R.M.) independently extracted data from eligible studies. Then, retrieved data were compared and discussed if discrepancies existed. A third author (S.W.) reviewed entered data for accuracy. In case of unclear information, the original studies' authors were contacted to provide additional clarification.

Data items
We considered studies eligible if they presented at least one of the following economic evaluation outcomes: • Cost analysis of interventions (CAI): estimation of the costs of an intervention's implementation. It can include direct costs (costs of resources used to design and implement an intervention, such as personnel time, facility rent, supplies, and medications), productivity losses (impacts of patient participation in an intervention, such as work time lost or leisure-time lost due to participation in the intervention) and intangible costs (non-financial costs, such as pain and suffering, which impose a major burden on individuals). 18 • Cost-effectiveness analysis (CEA): comparison between the costs and the effectiveness of two or more interventions with effectiveness measured in the same units. The incremental costeffectiveness ratio (ICER) is used to compare interventions-the difference in costs divided by the difference in health effects. Health effects are frequently measured through quality-adjusted life-years (QALYs) gained, disability-adjusted life-years (DALYs) averted, reduction of glycated hemoglobin, increase in daily steps, reduction in body fat, etc. 19 Generally, when the effectiveness is measured through QALYs, the term cost-utility analysis (CUA) can be used. 15 • Cost-benefit analysis (CBA): comparison of the costs (including those of implementing an intervention) and benefits (including those resulting from an intervention, such as medical costs averted, productivity gains and the monetized value of health improvements) of an intervention. The unity of analysis is monetary. 18 For each study, we summarized the following characteristics: first author, year of publication, country, design, intervention and comparison groups (type, duration, measurement, mode of delivery), study length, setting, condition (e.g. T2D vs multimorbidity of T2D), sample size (including sample size for each group, if available), and participants' age and sex. In addition, we extracted the following methodological information from the studies: the perspective of the analysis, type of economic evaluation, cost analysis, and health outcomes. Finally, we extracted the key findings and the authors' interpretation of the economic evaluation.

Study quality assessment
The assessment of the reporting quality of economic evaluation studies was performed by two independent authors (A.B. and R.M.), using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. 20 This statement consists of a 24item checklist subdivided into six main categories: (i) title and abstract; (ii) introduction; (iii) methods; (iv) results; (v) discussion; and (vi) other.

Effect measures
CAI usually considers the total cost of the interventions' implementation.
For CBA, the expected monetary benefits of the intervention are subtracted from the total cost of the interventions' implementation.
For CEA (including CUA), interventions can be classified as costsaving (an intervention that generates a similar health outcome with fewer costs than the comparison intervention) or cost-effective, according to the interpretation of the intervention impact in the variable that is used to measure the effectiveness (e.g. reduction in glycated hemoglobin, increase in daily steps, reduction in body fat, reduction in medications prescription). ICER-the difference in costs divided by the difference in health effects-is commonly used to measure cost-effectiveness and cost-utility, and it can be compared with thresholds based on per capita national incomes, benchmark interventions, or league tables. 19

Synthesis methods
We conducted a narrative synthesis of included studies.
For the comparison of national estimates from different years and in different currencies, we converted all to purchasing power parity (PPP) international dollars using conversion factors provided by the World Bank, 21 and considering the cost estimate year that studies provided. If a study did not mention the year used in cost analysis, we assumed the cost was the year of publication.
We did not perform meta-analysis to synthesize the results since we found many sources of heterogeneity across the studies. 22

Study selection
A total of 5323 references were identified in the initial search in electronic databases. After the duplicated studies (n ¼ 1514) were removed, 3809 studies remained. After screening for the title and abstract, 3508 papers were excluded, and 301 studies were eligible for full-text reading, from which 291 were removed. Thus, the selection process resulted in the inclusion of 10 studies in the qualitative synthesis ( figure 1).

Study characteristics
The study characteristics included in this review are shown in table 1.
All studies were published in English, between 1988 and 2021. Half of the studies were conducted in the USA [23][24][25] and Canada. 26,27 Seven studies were randomized controlled trials (RCT) 23,24,26,[28][29][30][31] and three were quasi-experimental studies. 25,27,32 All studies included interventions conducted in the community settings, although one study also included a hospital setting. 30 The length for included studies varied from 14 weeks to 24 months.
Most of the comparator groups included participants who followed usual care, 24,[26][27][28]30,31 one study had education, 23 one included a walking program only 29 and one received a pedometer only. 27

Study quality assessment in studies
The assessment of methodological quality for each study is presented in Supplementary file S3.
Most of the studies adhered to the CHEERS checklist in the categories of title and abstract, introduction, discussion and other. All the studies did not comply with methods and results' items, especially the choice of model, assumptions and uncertainty characterization.

Results of individual studies and synthesis
Results of individual studies are presented in table 2. Four studies took the sole perspective of healthcare, 23,25,28,29 four studies combined healthcare and societal perspectives 24,26,31,32 and two studies the payer perspective. 27,30 Records idenƟfied from: Pubmed  Economic evaluation of physical activity interventions i59  Economic evaluation of physical activity interventions i61 Exercise adherence (number of hours of exercise completed), improvements in peak maximal oxygen uptake, glycated hemoglobin and quality of life; cost-effectiveness of exercise training compared with pharmacological therapy.
The total cost of administering the telemonitored exercise program was $27 300, or $1050 per patient.
Costs per patient are similar to the costs that would be borne by the patient for using low dose insulin ($800) and a blood pressure agent ($130) for 6 months. IG completed a mean weekly volume of 138 min, moderate intensity exercise, while CG patients completed 58 minutes weekly (P < 0.02). In the IG, peak of maximal oxygen uptake increased (5.5%), and treadmill time (18%) and maximum heart rate (3%) were significantly greater at 6 months, compared with CG (P ¼ 0.04). Glycated hemoglobin did not change significantly after 6 months (P ¼ 0.46). No significant between-group changes were seen for quality of life.
The amount invested in intervention is comparable with other health interventions and it improved some health outcomes.
Pepin et al., 2020 25 Healthcare CEA Costs • Direct costs: included the costs of medication. Net changes over 12 months in cost were calculated by subtracting the cost related to increases from the cost related to decreases in fills and associated costs for the prescriptions fills.
Changes in medication use and cost of medication classes commonly prescribed in the management of chronic conditions. After 12 months, participants reduced the number of active prescriptions by 25%, 65% had no change and 10% increased diabetes medication, a net change of 14% decrease in diabetes medications. Fifty-five percent of patients had a decrease in their overall number of fills, with an average associated cost decrease of $473 per fill, or $117.254 overall. A net reduction was found in diabetes medications ($2.212).
Intervention is cost-saving. (continued) i62 European Journal of Public Health CAI, cost analysis of interventions; CBT, cognitive behavioral therapy; CEA, cost-effectiveness analysis; CG, comparator group; CUA, cost-utility analysis; IG, intervention group; MET, metabolic equivalent of task; PA, physical activity; QALYs, quality-adjusted life years; T2D, type 2 diabetes.
All studies included estimates of direct healthcare costs of physical activity interventions. Direct costs included medical costs (outpatient care, laboratory testing, expenses with medications, hospitalizations and emergency care). Four studies also provided indirect costs, 24,28,31,32 and included periods of not working, job loss and unemployment, and participants' time spent in physical activity sessions.
Regarding economic evaluation, nine studies included CEA, 24-32 and two studies used CUA. 23,31 No CBA was identified in this review.
Physical activity interventions were reported as being cost-saving in four studies, 24,25,28,32 six were considered cost-effective 24,26,27,[29][30][31] and two with cost-utility (table 3). 23,31 Discussion This systematic review summarized the available evidence on economic evaluation studies of physical activity interventions in the context of T2D control. Of the 10 studies included, nine were conducted in high-income countries, and only one was in a middle-income country (Malaysia). 30 Overall, we found that physical activity interventions are a worth investment for T2D control. Four interventions were considered cost-saving, 24,25,28,32 six were considered cost-effective 24,26,27,[29][30][31] and two were considered to have cost-utility. 23,31 In the literature, we can find other examples of interventions that are cost-effective in T2D management. Examples include interventions for hypertension control (angiotensin-converting enzyme inhibitor therapy for intensive compared with standard hypertension control); multicomponent interventions for diabetic risk factors control and early detection of complications, compared with standard glycemic control for persons with T2D; intensive lifestyle interventions to prevent T2D among persons with impaired glucose tolerance, compared with standard lifestyle recommendations; annual screening for diabetic retinopathy and ensuing treatment in persons with T2D, compared with no screening. 14,15 Despite the encouraging findings on the investment of physical activity interventions for T2D control highlighted in the current review, it should be noted that only four studies used glycated hemoglobin as the endpoint of T2D control. [28][29][30]32 Other studies used endpoints such as a change in daily steps 27 or a change in exercise volume 29,31 that can indirectly produce health benefits in people with T2D. However, these changes may not be sufficient to improve glycated hemoglobin, as noted by Marios et al. 29 Consistent in this review, combined aerobic and resistance exercise programs showed cost-effectiveness when compared with the usual care. 26,30 These results align with the physical activity guidelines for individuals with T2D, which recommend the inclusion of aerobic, resistance, flexibility and balance exercise training. 2,3 These findings also encourage decision makers to allocate resources to multi-modal physical activity interventions.
The reported costs of three interventions were around $1000 per participant, 23,27,29 which is a promising finding since it is similar to the annual per capita expenditure ($1423 in 2012 US dollars) on prescription medications for persons with T2D in the USA. 33 Additionally, costs are likely to decrease over time with, for example, the reduction of the prescribed medication for T2D and cardiovascular risk factors. 25,32 Moreover, regular practice of physical activity contributes to preventing and managing cognitive and mental health conditions and improving physical function across the lifespan. 34,35 In this review, most studies took a healthcare perspective. [23][24][25][26]28,29,31,32 Despite being very relevant for policymakers, upcoming studies should consider the societal perspective, which incorporates the economic impact on society, including the health sector (direct costs to public and private healthcare systems), non-health sector (indirect costs or productivity losses) and households (impact on usual activities). 36 By taking a societal perspective, the economic evaluation will be relevant to stakeholders from different sectors, considering that physical activity interventions may involve non-health sectors and the costs of physical inactivity are borne by different sectors of the society.
This study has several limitations that need to be addressed. First, high heterogeneity in interventions type, design and delivery was noted in the included studies, which may explain the differences in the economic measures. Second, similar to a previous systematic review of physical activity-related cost-of-illness analysis, important information, such as time horizon, assumptions, sensitivity analyses, discounting, uncertainty, economic perspective, physical activity and economic measures calculation, was often not reported. 11 Incomplete reporting has further complicated comparison between studies. Reporting of future studies should follow the best-practice standards for economic evaluation studies, such as the CHEERS statement. 20 Moreover, recruitment costs were not considered in the majority of the studies, which may have resulted in the underestimation of intervention costs, which is an important point of consideration if programs are scaled up. Third, we did not include multicomponent interventions (such as diet plus exercise), which seem to be more effective and cost-effective for T2D control. 37 Future research should involve larger studies with robust designs to establish the effects of physical activity interventions on T2D management and its cost-effectiveness, increase the reliability of findings and, ultimately, promote their use by policymakers.
It would also be important to investigate the impact of physical activity interventions on long-term outcomes related to T2D, namely in the incidence of cardiovascular diseases, micro-and macrovascular complications, years of life lost, and mortality. Furthermore, it was possible to note that long-term follow-up studies tend to be more cost-effective given that health benefits often last beyond the study period.

Conclusion
In conclusion, this systematic review found that physical activity interventions are a worth investment for type 2 diabetes management. However, due to the studies' heterogeneity, it is challenging to compare interventions across studies.
Studies with a societal perspective and robust analysis over wider time horizons are needed to explore the potential of physical activity interventions in the effectiveness and cost-effectiveness of T2D management over the long term. This will allow for efficient resource allocation by policymakers across the sectors involved in implementation programs.  26 Cost-effectiveness Di Loreto et al., 2005 32 Cost-saving Johnson et al., 2015 27 Cost-effectiveness Kaplan, 1988 23 Cost-utility Kuo et al., 2021 24 Cost-saving Cost-effectiveness Marios et al., 2012 29 Cost-effectiveness Pepin et al., 2020 25 Cost-saving Sultana et al., 2018 30 Cost-effectiveness Taylor et al., 2020 31 Cost-utility Cost-effectiveness